PT  - JOURNAL ARTICLE
AU  - Niu Shin
AU  - Yun-Long Li
AU  - Song Mei
AU  - Kathy He Wang
AU  - Leslie Hall
AU  - Kamna Katiyar
AU  - Qian Wang
AU  - Gengjie Yang
AU  - Beth Rumberger
AU  - Lynn Leffet
AU  - Xin He
AU  - Mark Rupar
AU  - Kevin Bowman
AU  - Margaret Favata
AU  - Jun Li
AU  - Mike Liu
AU  - Yanlong Li
AU  - Maryanne Covington
AU  - Holly Koblish
AU  - Maxim Soloviev
AU  - Dana Shuey
AU  - Timothy Burn
AU  - Sharon Diamond
AU  - Jordan Fridman
AU  - Andrew Combs
AU  - Wenqing Yao
AU  - Swamy Yeleswaram
AU  - Gregory Hollis
AU  - Kris Vaddi
AU  - Reid Huber
AU  - Robert Newton
AU  - Peggy Scherle
TI  - INCB040093 Is a Novel PI3K<em>δ</em> Inhibitor for the Treatment of B Cell Lymphoid Malignancies
AID  - 10.1124/jpet.117.244947
DP  - 2018 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 120--130
VI  - 364
IP  - 1
4099  - http://jpet.aspetjournals.org/content/364/1/120.short
4100  - http://jpet.aspetjournals.org/content/364/1/120.full
SO  - J Pharmacol Exp Ther2018 Jan 01; 364
AB  - Phosphatidylinositol 3-kinase delta (PI3Kδ) is a critical signaling molecule in B cells and is considered a target for development of therapies against various B cell malignancies. INCB040093 is a novel PI3Kδ small-molecule inhibitor and has demonstrated promising efficacy in patients with Hodgkin’s lymphoma in clinical studies. In this study, we disclose the chemical structure and the preclinical activity of the compound. In biochemical assays, INCB040093 potently inhibits the PI3Kδ kinase, with 74- to >900-fold selectivity against other PI3K family members. In vitro and ex vivo studies using primary B cells, cell lines from B cell malignancies, and human whole blood show that INCB040093 inhibits PI3Kδ-mediated functions, including cell signaling and proliferation. INCB040093 has no significant effect on the growth of nonlymphoid cell lines and was less potent in assays that measure human T and natural killer cell proliferation and neutrophil and monocyte functions, suggesting that the impact of INCB040093 on the human immune system will likely be restricted to B cells. INCB040093 inhibits the production of macrophage-inflammatory protein-1β (MIP-1beta) and tumor necrosis factor-β (TNF-beta) from a B cell line, suggesting a potential effect on the tumor microenvironment. In vivo, INCB040093 demonstrates single-agent activity in inhibiting tumor growth and potentiates the antitumor growth effect of the clinically relevant chemotherapeutic agent, bendamustine, in the Pfeiffer cell xenograft model of non-Hodgkin’s lymphoma. INCB040093 has a favorable exposure profile in rats and an acceptable safety margin in rats and dogs. Taken together, data presented in this report support the potential utility of orally administered INCB040093 in the treatment of B cell malignancies.